Analysis of MYH Tyr165Cys and Gly382Asp variants in childhood leukemias

Excerpt

DNA-repair gene mutations have been suspected as being a predisposing factor in the development of leukemia (Horwitz 1997). Our group identified one of the first examples of a DNA-repair gene mutation to be causally linked to childhood hematological malignancies and neurofibromatosis type I, which involves a homozygous germ-line mutation in the mismatch repair (MMR) gene MLH1 (Ricciardone et al. 1999; Wang et al. 1999). Subsequently, homozygous inactivation of MSH2, another MMR gene, was also found to be associated with early onset leukemia (Whiteside et al. 2002). It is well known that heterozygous germ-line mutations in the MMR pathway genes MLH1, MSH2, PMS2, PMS1, and MSH6 lead to hereditary non-polyposis colorectal cancer (HNPCC) (Peltomaki 2001). Thus, tumorigenesis through an "MMR deficiency pathway" appears to be associated with two different disease phenotypes which are dependent on the status of the germ-line mutation: (a) HNPCC when the mutation is present on only one allele (heterozygous), and (b) hematological malignancies when the mutation(s) is present on both alleles (homozygous or compound heterozygous). …